Osteoporosis is a major and growing health care problem that responds inadequately to standard pharmacologic therapy. Because of its low bone mineral density, osteoporotic bone is mechanically weak and fractures more easily than normal bone. Moreover, fracture repair is compromised in osteoporotic patients. The work described in this Phase I STTR proposal aims to develop a gene delivery vector laden nanostructured calcium phosphate (nCaP) substrate for improving the healing of fractures in osteoporotic bone, as well as a prophylactic treatment for bones that are at risk fracture. The proposed technologies emerge from a fusion of materials science, using expertise available at Angstom Medica, and gene transfer, using expertise available at the Center for Molecular Orthopaedics, Harvard Medical School. [unreadable] [unreadable] The central hypothesis of this project is that a nCaP material can (1) provide mechanical stability locally at a site of osteoporosis and (2) effectively and efficiently deliver vectors carrying osteoregenerative genes to improve the rate of healing of osteoporotic fractures and the mechanical properties of the healed bone. For this phenomena to occur, the nCaP substrate should (i) sustainably and (ii) controllably release gene delivery vectors in a localized and targeted manner. Through this targeted and controlled vector release, genes will be delivered to local osteoprogenitor cells, enhancing their ability to differentiate into osteoblasts and synthesize new bone in areas prone to osteoporotic fractures. The nCaP will also behave as a scaffold to encourage osteogenesis and, eventually, will be resorbed and replaced by host bone. [unreadable] [unreadable] Two fundamental requirements must be fulfilled to demonstrate feasibility of this technology: First, methods for associating vectors with nCaP in such a way as to permit efficient, sustained gene transfer to adjacent cells must be developed Second, enhanced formation of bone when the appropriate genes are transferred by these methods must occur. Both of these requirements will be scrutinized in the proposed investigations. In vitro assays will be used to develop methods for associating the vectors appropriately with the nCaP. In vivo assays, employing a rat femoral defect model, will be used to determine enhanced bone formation. [unreadable] [unreadable] Thus the Specific Aims are: [unreadable] 1. To develop processes for associating plasmid DNA and AAV with nCaP and controlling gene delivery by altering the density, pore size and surface chemistry of the nCaP-vector construct. [unreadable] 2. To evaluate the ability of nCaP-vector constructs to enhance osteogenic responses in vivo. [unreadable] [unreadable]